Biology Reference
In-Depth Information
1. THE GROWTH INHIBITORY PROTEINS IN THE CNS
SIGNAL TO RHO
1.1. Rho is a key to regeneration
Over the past 30 years, many components and signaling cascades that block
axon regeneration in the adult central nervous system (CNS) have been
elucidated (
Moore & Goldberg, 2010; Schwab, 2002, 2010
). Axon
behavior after injury in the CNS is influenced by intrinsic signals specific
to cell type together with environmental influences in the extracellular
environment. Axon growth during CNS development and during axon
regeneration in the injured CNS differs because neurons change as they
mature and also because there is a strong influence from growth
inhibitory molecules in the adult CNS environment.
In the 1980s, experiments by Aguayo and colleagues used peripheral
nerve grafts that were inserted into the brain or spinal cord to show
that CNS neurons have the capacity to regrow and highlighted that diverse
classes of CNS neurons have the potential to regenerate when given a
permissive growth environment (
Aguayo et al., 1991
). Another step forward
in our understanding of axon regeneration in the CNS was the discovery by
Schwab and colleagues that the CNS environment did not simply lack
growth-promoting molecules, but that growth inhibitory molecules existed
to block axon growth (
Schwab, Kapfhammer, & Bandtlow, 1993
). In a
separate field of study, an important discovery was that Rho signaling pro-
teins regulate the dynamics of cytoskeleton and cell motility (
Hall, 1996;
Hall & Lalli, 2010
). These fields of neuroscience and cell biology
converged with the discovery that the activation state of Rho is a critical
intracellular signaling determinant
for axon growth (
Lehmann et al.,
1999; Liu & Strittmatter, 2001
).
It has long been appreciated that in the peripheral nervous system, trans-
ected axons form growth cones immediately after injury, but in the CNS
they ultimately form retraction bulbs. We rationalized that if Rho is impor-
tant to control the cytoskeleton in nonneuronal cells, then it could also
regulate the growth cone cytoskeleton. In early studies, we demonstrated
that Rho colocalizes to points of substrate contact called point contacts in
growth cones (
Renaudin, Lehmann, & McKerracher, 1998
). We further
demonstrated using video microscopy that growth inhibitory proteins do
cause growth cone collapse and a single filopodial contact with beads coated
with CNS inhibitors was sufficient to completely stall axon growth (
Shibata
